How popular steroids can mess up some cancer treatments

Immunotherapy is one of the newest and most powerful weapons against cancer. This prompts the immune system to recognize the tumor as an intruder in the body and attack it. But not all patients respond well to immunotherapy. Why? Scientists aren’t always sure.

Occasionally, immunotherapy patients experience side effects that can be treated with steroids called glucocorticoids (GC). GCs are often used to regulate immune responses in conditions such as asthma, Crohn’s disease, and even COVID-19. But how they work is also a mystery.

Now, Cold Spring Harbor Laboratory (CSHL) researchers may be closer to answering both questions. Their new research suggests GC may indirectly cause some of the failures of immunotherapy treatments by promoting the production of a protein called Cystatin C (CyC). Higher CyC levels are associated with poorer outcomes from this type of therapy.

CSHL Assistant Professor Tobias Janowitz said, “GC is a very strong immune suppressor and as a result is used to treat autoimmunity,” which is when the immune system attacks healthy cells. “We have previously shown that GC can also impair cancer immunotherapy. Now, this might be a clue to how they do it.

Janowitz’s lab studies the response of the whole body to cancer. For this research, he and Ph.D. student in his lab, doctor-turned-researcher Sam Kleeman, teams up with a third CSHL scientist, Assistant Professor Hannah Meyer, a quantitative biologist. Together, they analyzed the UK Biobank’s massive genetic dataset. How massive? Nearly 500,000 volunteers, including cancer patients. Kleeman also reached out to researchers overseas to collect more patient data.

The scientists found that patients who were more likely to produce CyC in response to GC had poorer overall survival rates. These patients are also less likely to benefit from treatment. This suggests CyC production in tumors may contribute to the failure of cancer immunotherapy.

To confirm CyC’s link to cancer, researchers turned to good old-fashioned lab work. In mice, they deleted the CyC-producing gene so that it was no longer present in cancer cells. They found that tumors without CyC grew more slowly.

“It’s really powerful to come from multiple angles and support findings through multiple approaches,” Meyer said. “Intelligent genetic models give us some indication of which experiments are designed to help us answer questions about what these molecules do.”

Janowitz said he plans to continue studying CyC. He hopes it can be of great help to patients in the future.

“The research has given me impetus to know more about the function of this molecule, particularly in the context of cancer immunotherapy,” he said. “Perhaps its function could be targeted to increase the success of cancer immunotherapy.”